General procedure for the synthesis of 4-(ethoxymethyl)phenol from ethanol and p-hydroxybenzyl alcohol: refer to the operation of Example 2, but substitute ethanol for methanol. After completion of the reaction, the residue was purified by reduced pressure distillation (boiling point: 110-119°C/1.5 Torr) to obtain 4-ethoxymethylphenol in 75% yield and 98% HPLC purity. The operation was as follows: in a 200 mL three-necked flask equipped with a thermometer, a three-way stopper and a stirrer, 15.0 g (0.12 mol) of p-hydroxybenzyl alcohol and 69 g of ethanol were added under nitrogen protection, followed by 0.06 g of nitromethane. A mixed solution consisting of 0.45 g of hydrochloric acid and 3.0 g of ethanol was slowly added dropwise under stirring at room temperature, and then the reaction mixture was stirred at 35 °C for 3 hours. At the end of the reaction, HPLC analysis showed an area percentage of 99%. Next, a mixed solution comprising 0.38 g of imidazole (manufactured by Aldrich Co., Ltd.) and 1.1 g of ethanol was added dropwise for neutralization, followed by concentration under reduced pressure to remove ethanol. To the concentrate, 60 g of isopropyl ether (produced by Nacalai Tesque, Inc.) and 22.5 g of water were added and the organic layer was further washed with 27 g of water and 0.26 g of acetic acid (produced by Nacalai Tesque). After washing the organic layer twice with water, the organic layer was concentrated, the crystal seed was added and slowly cooled to about 8°C. The precipitated crystals were filtered and dried to give 12.0 g (yield: 72%) of colorless 4-methoxymethylphenol with 99% HPLC purity.
